Central Dogma Theory and Mutations
The central dogma of life consists of two main steps; transcription and translation. The nucleotide sequence present in the genes is responsible for the proper transformation of information from DNA to the ribosomes for the synthesis of new proteins. The alterations in the nucleotide sequences can produce different types of mutations. Out of these many types of mutations, one is the frame-shift mutation. Frame-shift mutation occurs when one or more nucleotide is either deleted from or added to the coding part of the gene. It will result in the radically different sequence of amino acids, or truncated product by the formation of termination codons by frame-shift mutation. Frame-shift mutations occur in diseases like Cystic fibrosis (CF), Tay-Sachs disease, Cancers, Crohn’s disease, and many others. The frame-shift mutations can be detected by fluorescence and sequencing. The cure for diseases produced by frame-shift mutation is under consideration of research work.
What is central dogma?
Central dogma is the main process of the formation of the proteins from the nucleotide message of the DNA. Central dogma consists of the two main processes, which are transcription of DNA into the mRNA and translation of this mRNA into the protein.
What are mutations?
Mutations are the alternations in the codon sequences of the genes, which results in abnormal synthesis of protein products. There are many further divisions of the mutations, classified according to the extent of alternations and the mechanism of alternations. Frame-shift mutation is also a type of mutation resulting from the alternation in the nucleotide sequence of the coding genes.
If one or two nucleotides are either added to or deleted from the coding region of the coding sequence, it is termed as frame-shift mutation, as it changes the reading frame. The malformed product is the result of the radically altered amino acid sequence. The frame-shift mutation can also produce a truncated product due to the formation of termination codons.
The mutations resulting from nucleotide substitutions do not affect the neighboring codons of the DNA, but the mutations resulting from the insertions or deletions cause the entire reading frame of the gene to be changed.
Missense mutation resulting from frame-shift mutations
Two frame-shift mutations can cancel each other, as the addition of one nucleotide at a location on the gene sequence can be counterbalanced by the deletion of another nucleotide along the coding sequence. In such conditions, the result will be a missense mutation.
Frame-shift mutation is different from the single nucleotide polymorphism, in which the nucleotide is actually replaced rather than deleted or inserted. The frame-shift mutation will result in altered codon and different amino acids. In this way, the created polypeptide chain will either be too long or too short, and the polypeptide chain produced by the frame-shift mutation will not be functional.
If three nucleotides are added, the produced peptide will contain one more amino acid. Similarly, if three nucleotides are deleted, the resulting peptide will lose one amino acid. If three nucleotides are lost, the reading frame will still be maintained but it can result in serious pathological conditions.
Examples of Frame-shift mutations
- Cystic fibrosis (CF) is a hereditary disorder, in which the digestive and the pulmonary systems are affected. Its most common cause is the deletion of three nucleotides from the coding region of the gene. In cystic fibrosis, the loss of three nucleotides results in the loss of phenylalanine at the 508th position in the encoded protein. This mutation at the 508th position of protein prevents the normal folding of the trans-membrane conductance regulator protein (CFTR), which leads to its destruction by the proteasome. The cystic fibrotic trans-membrane regulator (CFTR) normally functions as a chloride channel in the epithelial cells. The loss of CFTR results in the production of sticky, thick secretions in the pancreas and the lungs, leading to digestive and lung deficiencies. This 508th position mutation is the cause of the disease in 70% of Caucasians.
- Tay-Sachs disease is a severe genetic disorder produced as a result of frame-shift mutation. In this disease, the susceptibility to certain classes of familial hypercholesterolemia and cancers is increased.
- The resistance to the infection by the HIV retrovirus was reported to be linked with frame-shift mutation in 1997.
- Cancers of the colorectal region are associated with frame-shift mutations. The incidence of frame-shift mutation occurs more in the regions of repeat sequence. Frame-shift mutations also play an important role in the development of breast and ovarian cancer due to over 500 mutations in chromosome 17 in the BRCA1 gene.
- Crohn’s disease is associated with the NOD2 gene due to insertion of cytosine at position 320. It is also the consequence of frame-shift mutation.
Detection of frame-shift mutations
Frame-shift mutations can be detected by Fluorescence and Sequencing. In the fluorescence method, fluorescently tagged DNA enables us, by means of base analogues, to study the local changes of the DNA sequence. While in sequencing method, pyrosequencing and Sanger sequencing are the two methods used for detecting frame-shift mutations.
Cures for diseases caused by frame-shift mutations
The cure for the diseases caused by the frame-shift mutations is rare. However, research work is being done worldwide for finding the different mechanisms of treatment. The proposed mechanisms of treatment involve gene therapy, antisense oligonucleotide, mediated exon skipping, and revertant mosaicism. The use of immunotherapy for the treatment of frame-shift mutations is also under consideration.